HIV in sub-Saharan Africa is almost exclusively transmitted by heterosexual sex. Prospective randomized clinical trials (RCTs) in Africa, including 2 conducted by Hopkins researchers in Uganda, demonstrate that adult male circumcision reduces HIV acquisition by 60% and herpes simplex virus-2 (HSV-2) acquisition." Little is known about the immunology and pathophysiology of the foreskin. We propose to describe the immunology of foreskin inflammation and assess its role in HIV and HSV-2 acquisition and transmission using data and foreskin specimens obtained from the circumcision RCTs. The Hopkins Uganda circumcision trials enrolled both HIV+ and HIV--index male subjects and their female partners and archived the surgical foreskin specimens. With this repository, we have a unique opportunity to evaluate this hypothesis and to understand inflammation in the foreskin. The K23 candidate, Dr. Kristine Johnson, has specific interests in HIV immunology and sexually transmitted infections. The proposal provides for structured training and mentorship support to develop a translational research program to explore these relationships. Using methods already developed by Dr. Johnson, she will define local lymphocyte populations within the foreskin tissues, by confocal microscopy and immunohistochemistry. Using tissue PCR, she will quantify and characterize associated inflammation patterns and tissue HIV and HSV-2 viral content. After this work is completed, using the rich data collected on index subjects and partners, she will assess the impact of the foreskin cellular components on HIV acquisition events among initially HIV-uninfected men and the impact of foreskin cellular and viral components on HIV transmission events to serodiscordant female partners. Kristine Johnson, MD, joined the faculty of Johns Hopkins University Division of Infectious Diseases in July 2008. This application integrates epidemiology and immunological approaches using a unique sample set to answer critical questions in HIV/HSV-2 transmission. There is an especially strong mentorship team of experts in HIV/STI transmission and prevention, including Drs. Jonathan Zenilman, Ronald Gray and Thomas Quinn. RELEVANCE: As a beginning, we propose here to evaluate relationships between foreskin inflammation, epithelial lymphocyte populations, cytokines and HIV and HSV-2 infection and transmission. The results of this work will lead to a better understanding of the male foreskin immune milieu and may inform the development of new modalities for targeted HIV and STI prevention.